The long-term goal of this research is to elucidate novel mechanisms of neurodegeneration related to the pathogenesis of progressive forms of multiple sclerosis (MS), a common cause of disability in United States Veterans. Considering there are no treatments for progressive MS, a comprehensive understanding of the role of neurodegeneration in its pathogenesis should lead to novel therapeutic strategies to treat MS, thereby reducing disability. The purpose of this proposal is to examine how antibodies to RNA binding proteins (RBPs) cause neurodegeneration in MS. RBPs are critical to the normal function of neurons and have been recently implicated in the pathogenesis of neurodegenerative disease like amyotropic lateral sclerosis and dementia. However, there are little data on the role that RBPs play in neurodegeneration in immune-mediated diseases like MS. Many studies have implicated a number of viral triggers as a cause of MS, yet, no single virus has been exclusively shown to cause MS. Given this, human and animal viral models of MS are used to study its pathogenesis. One example is human T-lymphotropic virus type-1 (HTLV-1) associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is similar clinically, pathologically, and immunologically to progressive MS and thus is a relevant model to study it. HAM/TSP patients were found to make antibodies to heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), an RBP overexpressed in neurons. Importantly, MS patients were also found to make antibodies to hnRNP A1. Anti-hnRNP A1 antibodies reduced neuronal firing and caused neurodegeneration in neuronal cell lines, suggesting that these antibodies are pathogenic. Further, microarray analyses of neurons exposed to anti-hnRNP A1 antibodies altered hnRNP A1 function and revealed novel pathways of neurodegeneration. Specifically, there was downregulation of RNA levels of the spinal paraplegia genes (SPGs). SPGs contribute to normal neuronal function and axonal transport. Dysregulation of axonal transport results in neurodegeneration. Mutations in SPGs cause hereditary spastic paraparesis, genetic disorders clinically indistinguishable from progressive MS and HAM/TSP. Thus, there is a strong association between involvement of SPGs in neurodegeneration and the clinical phenotype of progressive MS and HAM/TSP patients, who commonly develop spastic paraparesis. The objective of this grant is to examine how anti-hnRNP A1 antibodies cause neurodegeneration. This will be accomplished by completing the following specific aims: 1. Determine the sensitivity and specificity of anti-hnRNP A1 antibodies as a diagnostic test for MS. 2. Examine molecular interactions between hnRNP A1 and target genes to determine their role in neuronal function and neurodegeneration. 3. Test for the pathogenicity of anti-hnRNP A1 antibodies using in vivo models of neurodegeneration. A serum test that can diagnose MS has yet to be discovered. Our data indicate that anti-hnRNP A1 antibodies can be used to diagnose MS. Anti-hnRNP A1 antibodies might also contribute to neurodegeneration and the pathogenesis of MS. The combination of both a diagnostic and pathogenic immune reaction is of particular relevance and has the potential to make important contributions to the long- term care and outcomes of people with MS.